T-Cell Epitope Prediction: Rescaling Can Mask Biological Variation between MHC Molecules

Theoretical methods for predicting CD8+ T-cell epitopes are an important tool in vaccine design and for enhancing our understanding of the cellular immune system. The most popular methods currently available produce binding affinity predictions across a range of MHC molecules. In comparing results between these MHC molecules, it is common practice to apply a normalization procedure known as rescaling, to correct for possible discrepancies between the allelic predictors. Using two of the most popular prediction software packages, NetCTL and NetMHC, we tested the hypothesis that rescaling removes genuine biological variation from the predicted affinities when comparing predictions across a number of MHC molecules. We found that removing the condition of rescaling improved the prediction software's performance both qualitatively, in terms of ranking epitopes, and quantitatively, in the accuracy of their binding affinity predictions. We suggest that there is biologically significant variation among class 1 MHC molecules and find that retention of this variation leads to significantly more accurate epitope prediction.Author Summary: The use of prediction software has become an important tool in increasing our knowledge of infectious disease. It allows us to predict the interaction of molecules involved in an immune response, thereby significantly shortening the lengthy process of experimental elucidation. A high proportion of this software has focused on the response of the immune system against pathogenic viruses. This approach has produced positive results towards vaccine design, results that would be delayed or unobtainable using a traditional experimental approach. The current challenge in immunological prediction software is to predict interacting molecules to a high degree of accuracy. To this end, we have analysed the best software currently available at predicting the interaction between a viral peptide and the MHC class I molecule, an interaction that is vital in the body's defence against viral infection. We have improved the accuracy of this software by challenging the assumption that different MHC class I molecules will bind to the same number of viral peptides. Our method shows a significant improvement in correctly predicting which viral peptides bind to MHC class I molecules.